ADCI (5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine), a low- -affinity uncompetitive NMDA antagonist, is a broad- -spectrum anticonvulsant with a favorable side effect profile. However, the drug's clinical utility will be dependent upon its ability to maintain efficacy when it is administered to patients on a chronic basis. Therefore, we sought to determine if tolerance develops to the anticonvulsant activity of chronically administered ADCI using the mouse maximal electroshock (MES) test to assess seizure protection. In studies with chronic ADCI administration, it was observed that tolerance does occur, but that this is due to pharmacokinetic factors (enhanced first- pass metabolism) and does not result from a reduction in anticonvulsant efficacy. The mechanism of the low toxicity of ADCI is not well understood, but could relate, in part, to selective actions of the drug on distinct NMDA receptor subtypes. Preliminary studies indicated that ADCI produces a more potent block of NMDA receptors containing the alternatively spliced NR1111 subunit (which includes a 21-amino acid N- terminal insert coded by exon 5 of the NR1 gene) than NR1011 (which lacks this insert).